Infiltrating CD8+ T cells exacerbate Alzheimer's disease pathology in a 3D human neuroimmune axis model.

Brain infiltration of peripheral immune cells and their interactions with brain-resident cells may contribute to Alzheimer's disease (AD) pathology. To examine these interactions, in the present study we developed a three-dimensional human neuroimmune axis model comprising stem cell-derived neurons, astrocytes and microglia, together with peripheral immune cells. We observed an increase in the number of T cells (but not B cells) and monocytes selectively infiltrating into AD relative to control cultures. Infiltration of CD8+ T cells into AD cultures led to increased microglial activation, neuroinflammation and neurodegeneration. Using single-cell RNA-sequencing, we identified that infiltration of T cells into AD cultures led to induction of interferon-γ and neuroinflammatory pathways in glial cells. We found key roles for the C-X-C motif chemokine ligand 10 (CXCL10) and its receptor, CXCR3, in regulating T cell infiltration and neuronal damage in AD cultures. This human neuroimmune axis model is a useful tool to study the effects of peripheral immune cells in brain disease.

Rac1 mediates cadherin-11 induced cellular pathogenic processes in aortic valve calcification.

BACKGROUND: Calcific aortic valve disease (CAVD), a major cause for surgical aortic valve replacement, currently lacks available pharmacological treatments. Cadherin-11 (Cad11), a promising therapeutic target, promotes aortic valve calcification in vivo, but direct Cad11 inhibition in clinical trials has been unsuccessful. Targeting of downstream Cad11 effectors instead may be clinically useful; however, the downstream effectors that mediate Cad11-induced aortic valve cellular pathogenesis have not been investigated. APPROACH AND RESULTS: Immunofluorescence of calcified human aortic valves revealed that GTP-Rac1 is highly upregulated in calcified leaflets and is 2.15 times more co-localized with Cad11 in calcified valves than GTP-RhoA. Using dominant negative mutants in porcine aortic valve interstitial cells (PAVICs), we show that Cad11 predominantly regulates Runx2 nuclear localization via Rac1. Rac1-GEF inhibition via NSC23766 effectively reduces calcification in ex vivo porcine aortic valve leaflets treated with osteogenic media by 2.8-fold and also prevents Cad11-induced cell migration, compaction, and calcification in PAVICs. GTP-Rac1 and Trio, a known Cad11 binding partner and Rac1-GEF, are significantly upregulated in Nfatc1Cre; R26-Cad11Tg/Tg (Cad11 OX) mice that conditionally overexpress Cad11 in the heart valves by 3.1-fold and 6.3-fold, respectively. Finally, we found that the Trio-specific Rac1-GEF inhibitor, ITX3, effectively prevents Cad11-induced calcification and Runx2 induction in osteogenic conditions. CONCLUSION: Here we show that Cad11 induces many cellular pathogenic processes via Rac1 and that Rac1 inhibition effectively prevents many Cad11-induced aortic disease phenotypes. These findings highlight the therapeutic potential of blocking Rac1-GEFs in CAVD.

Lobar Gross Endobronchial Disease Predicts for Overall Survival and Grade 5 Pulmonary Toxicity in Medically Inoperable Early Stage Non-Small Cell Lung Cancer Patients Treated With Stereotactic Body Radiation Therapy.

PURPOSE: Stereotactic body radiation therapy (SBRT) is considered standard of care for medically inoperable early stage non-small cell lung cancer (ES-NSCLC). Central tumor location is a known risk factor for severe SBRT related toxicity. Bronchoscopy allows for visualization of the central airways prior to treatment. Five fraction SBRT approaches have been advocated to mitigate treatment induced toxicity. In this report, we examine the mature clinical outcomes of a diverse cohort of ES-NSCLC patients with both peripheral and central tumors treated with a conservative 5 fraction SBRT approach and evaluate the role of lobar gross endobronchial disease (LGED) in predicting overall survival and treatment-related death. METHODS: Medically inoperable biopsy-proven, lymph node-negative ES-NSCLC patients were treated with SBRT. Bronchoscopy was completed prior to treatment in all centrally located cases. The Kaplan-Meier method was used to estimate overall survival (OS), local control (LC), regional control (RC), distant metastasis free survival (DMFS) and disease-free survival (DFS). Overall survival was stratified based on clinical stage, histology, tumor location and LGED. Toxicities were scored according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0. RESULTS: From December 2010 to December 2015, 50 consecutive patients were treated uniformly with a 50 Gy in 5 fraction SBRT approach (tumor BED10 ≥ 100 Gy) and followed for a minimum of 5 years or until death. At a median follow up of 42 months for all patients, 3-year OS was 50%. Three-year OS did not statistically differ between stage I and stage II disease (51% vs. 47%; p=0.86), adenocarcinoma and squamous cell carcinoma (50% vs. 45%; p=0.68), or peripheral and central tumors (56% vs. 45%; p=0.46). Five central tumors were found to have LGED, and 3-year OS for this cohort was quite poor at 20%. Cox regression analysis identified LGED as a predictor of OS while controlling for age, stage and location (OR:4.536, p-value=0.038). Despite the relatively low dose delivered, treatment likely contributed to the death of 4 patients with central tumors. Lobar gross endobronchial disease was an independent predictor for grade 5 pulmonary toxicity (n=4, p=0.007). Specifically, 3 of the 5 patients with LGED developed fatal radiation-induced bronchial stricture. Three-year LC, RC, DMFS and DFS results for the group were similar to contemporary studies at 90%, 90%, 82% and 65%. CONCLUSIONS: Central location of ES-NSCLC is a well-established predictor for severe SBRT-related toxicity. Here we identify LGED as a significant predictor of poor overall survival and grade 5 pulmonary toxicity. The relatively high rates of severe treatment-related toxicity seen in patients with central ES-NSCLC may be due in part to LGED. Underlying LGED may cause irreparable damage to the lobar airway, unmitigated by SBRT treatment thus increasing the risk of severe treatment-related toxicity. These findings should be verified in larger data sets. Future prospective central ES-NSCLC clinical trials should require staging bronchoscopy to identify LGED and further assess its clinical significance.

Disparities in Breast Cancer Screening Uptake for Women With Mental Illness in the United Kingdom.

INTRODUCTION: Although there is evidence of disparities in breast cancer screening for women with mental illness in the U.S., there is a dearth of studies examining this association in the United Kingdom, where health care is provided free at the point of access. This population-based study examines the influence of mental illness, as assessed by the uptake of psychotropic medications, on breast screening uptake in the United Kingdom. METHODS: A cohort of 57,328 women identified from 2011 Census records within the Northern Ireland Longitudinal Study was followed through a single 3-year screening cycle (2011-2014) of the National Health Service Breast Screening Programme. Mental illness was identified by a receipt of psychotropic medication in the 3 months preceding screening invite. Individual- and household-level attributes were derived from Census records. Data were analyzed in 2019. RESULTS: More than a third of women received ≥1 prescription for psychotropic medication in the 3 months preceding screening invite. The odds of attendance in these individuals were reduced by 15% (OR=0.85, 95% CI=0.81, 0.88). Attendance was particularly low for women prescribed antipsychotics (OR=0.63, 95% CI=0.56, 0.70), anxiolytics (OR=0.61, 95% CI=0.57, 0.66), and hypnotics (OR=0.68, 95% CI=0.63, 0.72). CONCLUSIONS: These findings confirm the existence of significant disparities in breast screening uptake for women with mental illness. Targeted interventions are warranted to prevent avoidable breast cancer deaths in these individuals, especially given the increasing prevalence of mental illness.

Understanding how best to engage recreationists in biosecurity to reduce the impacts of tree diseases: a review.

Pests and diseases introduced from other countries are known to pose a threat to trees, woods and forests in many locations throughout the world. Once introduced they can be spread inadvertently by countryside visitors hiking, biking or riding along paths and trails through wooded areas. Engaging and communicating with these groups of countryside users to encourage and facilitate positive biosecurity behaviours is crucial for the future resilience of trees, woods and forests. This review draws on literature outlining principles for stakeholder engagement in forestry as well as evaluations of biosecurity campaigns from around the world. Key points are briefly presented for communicators aiming to encourage better biosecurity in the countryside. These include, the need to design campaigns based on the values and motivations of recreationists, using trusted information sources and understanding the importance of combining information with facilities so as to reduce the cost (in terms of effort and inconvenience) to hikers and other countryside users.

Does poor mental health explain socio-demographic gradients in breast cancer screening uptake? A population-based study.

BACKGROUND: Research from the USA indicates disparities in breast cancer screening uptake for women with poor mental health. However, no attempt has been made to examine the contribution of poor mental health to socio-demographic variations in breast screening uptake. The current study aims to examine the impact of self-reported chronic poor mental health on attendance at breast screening in the UK, and to what extent this explains socio-demographic inequalities in screening uptake. METHODS: Breast screening records were linked to 2011 Census records within the Northern Ireland Longitudinal Study. This identified a cohort of 57 328 women who were followed through one 3-year screening cycle of the National Health Service Breast Screening Programme. Information on mental health status, in addition to other individual and household-level attributes, was derived from the 2011 Census. Logistic regression was employed to calculate odds ratios (ORs) and 95% confidence intervals (CIs) of attendance at screening. RESULTS: 10.7% of women in the cohort reported poor mental health, and in fully adjusted analyses, these individuals were 23% less likely to attend breast screening (OR 0.77; 95% CI 0.73-0.82). Although poor mental health was a strong predictor of screening uptake, it did not explain the observed inequalities in uptake by socio-economic status, marital status, or area of residence. CONCLUSIONS: This study provides novel evidence of inequalities in breast screening uptake for women with chronic poor mental health in the UK. Targeted interventions are necessary to ensure equitable screening access and to enhance overall mortality benefit.

Disability as a predictor of breast cancer screening uptake: A population-based study of 57,328 women.

OBJECTIVE: Despite a growing body of evidence suggesting inequalities in breast cancer screening uptake in the United States for women with disabilities, few attempts have been made to examine whether this association applies to the United Kingdom. We conducted the first population-wide study investigating the impact of disability on uptake of breast cancer screening in Northern Ireland. METHODS: Breast screening records extracted from the National Breast Screening System were linked to the Northern Ireland Longitudinal Study. This identified a cohort of 57,328 women who were followed through one complete three-year screening cycle of the National Health Service Breast Screening Programme in Northern Ireland. The presence of disability was identified from responses to the 2011 Census. RESULTS: Within this cohort, 35.8% of women reported having at least one chronic disability, and these individuals were 7% less likely to attend compared with those with no disability (odds ratio 0.93; 95% confidence interval 0.89-0.98). Variation in the degree of disparity observed was evident according to the type and number of comorbid disabilities examined. CONCLUSION: This is the first population-wide study in Northern Ireland to identify disparities in breast screening uptake for women with chronic disabilities, in particular, those with multimorbidity. This is of particular concern, given the projected rise in the prevalence of disability associated with the ageing population.

Intergenerational understandings of personal, social and community assets for health.

Connecting local citizens of different ages in productive social activity is considered a pathway towards greater health. This research explores how older adults and young people interpret and access assets from their geographical community in relation to their well-being and the extent to which a process of intergenerational bridging contributes to the creation of additional assets for health. Data is presented from a process of place-mapping, interviews, observations and arts-based approaches to: a) understand how personal, social and community assets supported perceived health and wellbeing for the young children and older adults who participated; and b) explore the impact of intergenerational connection on enhancing social capital. The research utilised bonding, bridging and linking forms of social capital, across several interactions amongst 41 individuals who reside in the same geographical community (Victoria, Australia). Assets for health, common across generations and located within the same geographical community were identified. Social connections were strengthened through conversations, reflections and an integration of ideas facilitated through an arts-based approach. Findings suggest that through intergenerational connection and sharing of resources to support health, including the sharing of community assets, progress can be made towards community strengthening with implications for health and wellbeing.

Screen detection of ductal carcinoma in situ and subsequent incidence of invasive interval breast cancers: a retrospective population-based study.

BACKGROUND: The value of screen detection and treatment of ductal carcinoma in situ (DCIS) is a matter of controversy. At present, the extent to which the diagnosis and treatment of DCIS could prevent the occurrence of invasive breast cancer in the future is not clear. We sought to estimate the association between detection of DCIS at screening and invasive interval cancers subsequent to the relevant screen. METHODS: We obtained aggregate data for screen-detected cancers from 84 local screening units within 11 regional Quality Assurance Reference Centres in England, Wales, and Northern Ireland from the National Health Service Breast Screening Programme. Data for DCIS diagnoses were obtained for women aged 50-64 years who were invited to and attended mammographic breast screening from April 1, 2003, to March 31, 2007 (4 screening years). Patient-level data for interval cancer arising in the 36 months after each of these were analysed by Poisson regression with invasive interval cancer screen detection rate as the outcome variable; DCIS detection frequencies were fitted first as a continuous and then as a categorical variable. We repeated this analysis after adjustment with both small size and high-grade invasive screen-detected cancers. FINDINGS: We analysed data for 5,243,658 women and on interval cancers occurring in the 36 months after the relevant screen. The average frequency of DCIS detected at screening was 1·60 per 1000 women screened (median 1·50 [unit range 0·54-3·56] [corrected to] per 1000 women). There was a significant negative association of screen-detected DCIS cases with the rate of invasive interval cancers (Poisson regression coefficient -0·084 [95% CI -0·13 to -0·03]; p=0·002). 90% of units had a DCIS detection frequency within the range of 1·00 to 2·22 per 1000 women; in these units, for every three screen-detected cases of DCIS, there was one fewer invasive interval cancer in the next 3 years. This association remained after adjustment for numbers of small screen-detected invasive cancers and for numbers of grade 3 invasive screen-detected cancers. INTERPRETATION: The association between screen-detected DCIS and subsequent invasive interval cancers suggests that detection and treatment of DCIS is worthwhile in prevention of future invasive disease. FUNDING: UK Department of Health Policy Research Programme and NHS Cancer Screening Programmes.

Uptake of breast screening is influenced by current religion and religion of upbringing.

Research has shown that individuals with a current religious affiliation are more likely to use preventive health services. The aim of this study was to determine whether breast screening uptake in Northern Ireland is higher amongst women with a current affiliation to an organised religion and, for those with no current affiliation, to examine whether their religion of upbringing is associated with uptake of breast screening. The Northern Ireland Longitudinal Study (NILS) was used to link Census and national breast screening data for 37,211 women invited for routine breast screening between 2001 and 2004. Current religious affiliation, religion of upbringing and other demographic and socio-economic characteristics were as defined on the Census form. Multivariate logistic regression was used to determine the relationship between religion affiliation and attendance. Uptake of breast screening is about 25% lower for those without a current religious affiliation. There are modest differences between Catholics and Protestants, with the latter about 11% more likely to attend for screening. For those with no current religion, the religion of upbringing appears to positively influence attendance rates. These differences remain after adjustment for all of the socio-demographic and socio-economic factors that have been shown to influence uptake rates of breast screening in the UK to date. Record linkage is an efficient way to examine equity across demographic characteristics that are not routinely available. The lower uptake amongst those with no religious affiliation may mean that screening services may find it difficult to maintain or improve uptake rate in an increasingly secularised society.

Using record linkage to monitor equity and variation in screening programmes.

BACKGROUND: Ecological or survey based methods to investigate screening uptake rates are fraught with many limitations which can be circumvented by record linkage between Census and health services datasets using variations in breast screening attendance as an exemplar. The aim of this current study is to identify the demographic, socio-economic factors associated with uptake of breast screening. METHODS: Record linkage study: combining 2001 Census data within the Northern Ireland Longitudinal Study (NILS) with data relating to validated breast screening histories from the National Breast Screening System. A cohort was identified of 37,059 women aged 48-64 at the Census who were invited for routine breast screening in the three years following the Census. All cohort attributes were as recorded on the Census form. RESULTS: The record linkage methodology enabled the records of almost 40,000 of those invited for screening to be analysed at an individual level, exceeding the largest published survey by a factor of ten. This produced a more robust analysis and demonstrated (in fully adjusted models) the lower uptake amongst non-married women and those in the lowest social class (OR 0.74; 95%CI 0.66, 0.82), factors that had not been reported earlier in the UK. In addition, with the availability of both individual and area information it was possible to show that the much lower screening uptake in urban areas is not due to differences in population composition suggesting unrecognised organisational problems. CONCLUSIONS: Linkage of screening data to Census-based longitudinal studies is an efficient and powerful way to increase the evidence base on sources of variation in screening uptake within the UK.

Capitalizing on deliberate, accidental, and GM-driven environmental change caused by crop modification.

The transgenic traits associated with the majority of commercial genetically modified crops are focused on improving herbicide and insecticide management practices. The use of the transgenic technology in these crops and the associated chemistry has been the basis of studies that provide evidence for occasional improvement in environmental benefits due to the use of less residual herbicides, more targeted pesticides, and reduced field traffic. This is nicely exemplified through studies using Environmental Impact Quotient (EIQ) assessments. Whilst EIQ evaluations may sometimes illustrate environmental benefits they have their limitations. EIQ evaluations are not a surrogate for Environmental Risk Assessments and may not reflect real environmental interactions between crops and the environment. Addressing the impact cultivated plants have on the environment generally attracts little public attention and research funding, but the introduction of GM has facilitated an expansion of research to address potential environmental concerns from government, NGOs, industry, consumers, and growers. In this commentary, some evidence from our own research and several key papers that highlight EIQ assessments of the impact crops are having on the environment are presented. This information may be useful as an education tool on the potential benefits of GM and conventional farming. In addition, other deliberate, accidental, and GM-driven benefits derived from the examination of GM cropping systems is briefly discussed.

Are caregiving responsibilities associated with non-attendance at breast screening?

BACKGROUND: Previous research showed that deprived individuals are less likely to attend breast screening and those providing intense amounts of informal care tend to be more deprived than non-caregivers. The aim of this study was to examine the relationship between informal caregiving and uptake of breast screening and to determine if socio-economic gradients in screening attendance were explained by caregiving responsibilities. METHODS: A database of breast screening histories was linked to the Northern Ireland Longitudinal Study, which links information from census, vital events and health registration datasets. The cohort included women aged 47 - 64 at the time of the census eligible for breast screening in a three-year follow-up period. Cohort attributes were recorded at the Census. Multivariate logistic regression was used to examine the relationship between informal caregiving and uptake of screening using STATA version 10. RESULTS: 37,211 women were invited for breast screening of whom 27,909 (75%) attended; 23.9% of the cohort were caregivers. Caregivers providing <20 hours of care/week were more affluent, while those providing >50 hours/week were more deprived than non-caregivers. Deprived women were significantly less likely to attend breast screening; however, this was not explained by caregiving responsibilities as caregivers were as likely as non-caregivers to attend (Odds Ratio 0.97; 95% confidence intervals 0.88, 1.06). CONCLUSIONS: While those providing the most significant amounts of care tended to be more deprived, caregiving responsibilities themselves did not explain the known socio-economic gradients in breast screening attendance. More work is required to identify why more deprived women are less likely to attend breast screening.